Theophylline

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Secondary source

Data source

Reference

Reference 1

Reference Type:

review article or handbook

Title:

Coffee, Tea, Mate, Methylxanthines and Methylglyoxal

Author:

IARC Monographs on the evaluation of carcinogenic risks to humans

Year:

1991

Bibliographic source:

IARC Monographs, Vol. 51, 1991, pp 391-419.

Reference 2

Reference Type:

secondary source

Title:

Coffee, Tea, Mate, Methylxanthines and Methylglyoxal

Author:

IARC Monographs on the evaluation of carcinogenic risks to humans

Year:

1991

Bibliographic source:

IARC Monographs, Vol. 51, 1991, pp 391-419; cited in: OECD SIDS for CAS-No. 58-55-9, 2003.

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

Review

Test material

Test material information

Constituent 1

Reference substance name:

Theophylline

EC Number:

200-385-7

EC Name:

Theophylline

Cas Number:

58-55-9

Molecular formula:

C7H8N4O2

IUPAC Name:

1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione

Details on test material:

- Name of test material (as cited in study report): Theophylline

Test animals

Species:

other: different animal species

Strain:

not specified

Sex:

not specified

Administration / exposure

Route of administration:

other: different route of administration

Duration and frequency of treatment / exposure:

variable

Doses / concentrations

Remarks:

Doses / Concentrations:
variable

No. of animals per sex per dose / concentration:

no data

Control animals:

not specified

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Theophylline was rapidly and completely absorbed from the digestive tract of different species (dogs, rats, cats).

Details on distribution in tissues:

Transport of theophylline from blood to the intestinal lumen was demonstrated in rats. After intravenous administration, theophylline was distributed to all organs of rats except adipose tissue. Whole body autoradiographs showed no accumulation in any specific tissue after oral administration to rats.
Theophylline readily crosses the placenta in rats and rabbits and no blood-brain barrier was observed in fetuses of the rat.

Details on excretion:

Theophylline is metabolized in the liver, mainly by the microsomal system. The metabolites are excreted into the bile and eliminated with the urine.

Metabolite characterisation studies

Details on metabolites:

The theophylline metabolism in rats gives the following composition: Unchanged theophylline (35% of urinary radioactivity) and 1,3-dimethyluric acid (34%) are the main compounds excreted in urine, followed by 1-methyluric acid (18%), 3-methylxanthine (3%) and unidentified polar metabolites
(4.8%). Theophylline metabolism was impaired in rats at day 18 of gestation, as shown by increased excretion of theophylline (73%); this was explained by a decreased formation of 1,3-dimethyluric acid (-68%) and 1-methyluric acid (-30%).

Any other information on results incl. tables

Plasma half-life is between 1.2 - 4 hours in rats, 3.8 - 5.5 hours in rabbits and 6 -11.5 hours in dogs and strongly dependent on protein binding and dose. A significant increase in the half-time of theophylline was found in pregnant rabbits and rats. The half-time in newborn rabbits was approximately 15 times longer than in adult animals.